Substituted thiadiazoles



3,332,942 SUBSTITUTED THIADIAZOLES J. Breivogel, Glen Ridge, N.J.,assignor to White Philip a corporation of Laboratories, Inc.,Kenilworth, N..I.,

New Jersey No Drawing. Filed Nov. 2, 1962, Ser. No. 235,117

6 Claims. (Cl. 260-23935) This invention relates to compositions ofmatter classified in the field of chemistry as -alkoxyalkyl-substituted2-(4-aminophenylsulfonamido)-1,3,4-thiadiazoles and the process formaking and using such compositions.

The invention sought to be patented, in its composition aspect, isdescribed as residing in the concept of a chemical compound having amolecular structure in which there is attached to a 1,3,4-thiadiazolenucleus at the 2-position a 4-aminophenylsulfonamido group, or itshereinafter disclosed equivalent, and at the 5-position an alkoxyalkylgroup, or its hereinafter disclosed equivalent.

The invention sought to be patented, in its process aspect, is describedas residing in the concept of using the tangible embodiment of acomposition of matter having a molecular structure in which there isattached to a 1,3,4- thiadiazole nucleus at the 2-position a4-aminophenylsulfonamido group, or its hereinafter disclosed equivalent,and at the 5-position an alkoxyalkyl group, or its hereinafter disclosedequivalent, by administering such composition as an essential activeingredient of a pharmaceutical formulation for the application ofhyperglycemic therapy.

The tangible embodiments of the invention possess the inherent applieduse characteristics of exerting an antihyperglycemic effect as evidencedby in vivo evaluation.

As used herein, the term alkoxyalkyl group means lower alkoxy-loweralkyl radicals, including the straight and branched chain radicals,among which are, for purpose of illustration but without limiting thegenerality of the foregoing, the following:

where n= 1-5 The manner and process of making and using the inventionwill now be generally described so as to enable a person skilled in theart of chemistry to make and use the same, as follows:

The Z-amino-S-alkoxyalkyl-1,3,4-thiadiazole starting materials (III) canbe prepared according to the followin g general procedure which involvesthe condensation and cyclization of thiosemicarbazide (I) with analkoxyalkyl carboxylic acid, such as methoxyacetic acid (II), in thePatented July 25, 1967 presence of phosphorous oxychloride. Thisreaction is illustrated as follows:

The reaction may be carried out under a reflux condenser and withstirring, by the dropwise addition of approximately one mole ofphosphorous oxychloride to a cooled mixture of one mole of alkoxyalkylcarboxylic acid and one mole of thiosemicarbazide at such rate that thereaction temperature remains between 40 and C. The addition usuallyrequires 0.5 to 1.0 hour. When all the phosphorous oxychloride is added,the reaction temperature is raised to about 95 C. and stirring iscontinued for about 3-4 hours. Toward the end of the reaction when theevolution of HCl gas slows down, the reaction mixture may become toothick to stir. In this event stirring is stopped but heating iscontinued until evolution of HCl gas ceases. The warm reaction mixtureis dissolved in water, stirredwith decolorizing carbon and filtered. Thefiltrate'is cooled to about 5-l0 C. and the Z-amino-S-alkoxyalkyl-1,3,4-thiadiazole is precipitated by the addition of 10molarsodium hydroxide solution to pH 9-10. The crude product is filtered,washed with water and dried. It may be purified by recrystallizationfrom a suitable solvent such as ethyl acetate, n-butyl acetate,methanol, ethanols, dilute alcohols or water.

The alkoxyalkyl carboxylic acid intermediates employed in the abovereaction are generally known or are readily prepared by procedures knownto those skilled in the art. Thus, methoxyacetic acid (II), for example,is prepared by adding 2.0 moles of monochloroacetic acid in 200 ml. ofanhydrous methanol to a stirred solution of 4.1 gm. atoms of sodium in850 ml. of anhydrous methanol at such rate that the reaction mixture ismaintained at reflux temperature. When all the acid has been added,reflux is continued for approximately ten minutes and the methanol isthen removed by distillation. The methanol-free residue is stirred witha solution of approximately 225 ml. of concentrated hydrochloric acid in300 ml. of water. The free methoxyacetic acid is extracted with ether,the extract is dried over anhydrous sodium sulfate, the solvent isremoved by distillation and the crude methoxyacetic acid is purified bydistillation under vacuum. Other alkoxyalkyl carboxylic acids may beprepared by the same general procedure by substituting the appropriateacid and/or alcohol in place of the monochloroacetic acid and/or themethanol used above.

Preparation of the 2-(4aminosulfonamido)-5-alkoxyalkyl-1,3,4-thiadiazo1es of this invention isaccomplished by the condensation of 4-acetamido-benzenesulfonyl chloridewith a Z-amino-S-alkoxyalkyl-1,3,4-thiadiazole, prepared as illustratedabove, in the presence of a suitable organic solvent and pyrodinefollowed by the acid hydrolysis of the acetamido intermediate thusproduced.

The reaction is carried out by dissolving the Z-arnino-S-alkoxyalkyl-1,3,4-thiadiazole and at least one equivalent of atertiary base such as pyridine or triethylamine in dioxane, acetone orother suitable solvent, stirring the solution and adding one equivalentof 4-acetamidobenzenesulfonyl chloride in small proportions. During theaddition, the temperature is held at approximately 25- 40 C. and whenthe addition is completed, stirring is a continued at approximately 7090C; for about 1-4 hours to complete the reaction. The reaction mixture is:hen cooled to about 40 C. and poured into five to ten :imes its volumeof ice water with rapid stirring. The .esultant suspension is acidifiedto pH 12 with concenzrated hydrochloric acid and stirring is continueduntil :he precipitate becomes granular or crystalline. The crudel-(4-acetamidophenylsulfonamido) 5 alkoxyalkyl-l,3,4- :hiadiazole isseparated by filtration and, if desired, can 5e purified byrecrystallization from a suitable solvent lllCh as methanol, ethanol,isopropanol or dilutions of hese with water prior to hydrolysis.

Hydrolysis of the acetamido intermediate is efiected )y stirring onepart by Weight of the acetamido compound vith about ten parts by weightof 7% aqueous hydro- :hloric acid at approximately 90100 C. for a period)f about 0.5 to 2 hours. A solvent such as methanol, ethanol orisopropanol may be employed in the hydrol- 'sis of the less watersoluble derivatives. Upon comaletion of the hydrolysis, the resultinghot solution is tirred with a small amount of decolorizing carbon andiltered. The clear filtrate is cooled to approximately 5 0 C. andsufficient 10 molar sodium hydroxide is added 0 just redissolve theprecipitate which forms. The alkaine solution is then adjusted to aboutpH 4.05.0, by he addition of acetic acid and, after stirring at about C.for approximately 0.5 hour, the precipitated 2-(4-minophenylsulfonamido)-5-alkoxyalkyl 1,3,4 thiadizole crystals arefiltered off, washed with water and ried. The crude product is purifiedby recrystallization rom a suitable solvent such as methanol, ethanol,isoropanol or a dilution of these with Water.

According to the above process, for example, Z-amino--methoxymethyl-1,3,4-thiadiazole (III) is condensed Ilth4-acetamidobenzenesulfonyl chloride (IV) to yield(4-acetamidophenylsulfonamido) 5 methoxymethyl- ,3,4-thiadiazole (V)which, by acid hydrolysis is conerted into the desired2-(4-aminophenylsulfonamido)- -methoxymethyl-1,3,4-thiadiazole (VI).These reactions re illustrated as follows:

Although the instant invention has been particularly lustrated, and inthe subsequent examples will be illusated, with reference toS-alkoxyalkyl compounds, the xygen atom of these substituents may bereplaced by llfur. The corresponding 5 alkylmercapto alkyl comaunds soproduced have the same utility as the illusated 5-alkoxyalkyl compoundsand applicant considers )th type-s of compounds to be fully equivalent.

It will also be apparent to a chemist skilled in the art .at the novelcompounds of this invention are amphoric in nature and can be caused toform alkali metal .g. sodium, potassium, etc.) and acid addition (e.g.hy- 'ochloride, citrate, etc.) salts by methods well known in e art.These salts also are considered by applicant to be e full equivalents ofthe novel compounds disclosed )OVC.

The therapeutically active thiadiazoles of this invention .n beadministered orally in the form of tablets, elixirs, vpsules, and thelike. In tablet form, they are com- )unded with an inert pharmaceuticalcarrier which may Intain a suitable binder such as, for example, gums,arches and sugars. They may also be incorporated into gelatin capsuleand also formulated in elixirs which We the advantage of beingsusceptible to manipulations flavor by the addition of standard naturalor synthetic 4 flavoring materials. Preferably, these compositions areso proportioned as to afford a unit dosage of from 25 to 100 mg.

The following examples show typical tablet, capsule and elixirformulations incorporating the therapeutically active thiadiazoles ofthis invention. These formulations are illustrative merely and nolimitation is intended except as set forth in the appended claims:

TABLET FORMULATION Milligrams per Formula: tablet 2-(4-aminophenylsulfonamido) 5 n-butoxymethyl-1,3,4-thiadiazole 25.0Calcium phosphate dibasic (N.F. dihydrate) 75.0 Lactose 31.0 Starch,U.S.P. (10% w./W. paste) 3.0 Starch, U.S.P. (dry) 15.0 Magnesiumstearate, U.S.P 1.0

To prepare the tablets, blend the lactose, the dibasic calciumphosphate, /3 of the dry starch and the thiadiazole. Slowly add thestarch paste and mix until the mass is uniformly wetted (add water, ifnecessary to produce a wet mass). Pass the Wet mass through a 6 meshscreen and dry the resulting granulation at C. overnight. Pass the drygranulation through a 16 mesh screen; add the remainder of the starchand the magnesium stearate, and blend to a uniform mixture. Compress toa target weight of 150 mg. Coat the tablets if desired.

CAPSULE FORMULATION Milligrams per Formula: capsule 2(4-aminophenylsulfonamido) S-n-butoxymethyl-1,3,4-thiadiazole 25.0Lactose 385.0

Magnesium stearate 10.0

Prepare the capsules by passing the dry ingredients through a 30 meshscreen to break up lumps and blend until homogeneous. Fill No. 2 hardgelatin capsule to a target weight of 420 mg.

LIQUID SUSPENSION Grams Formula: per liter Veegum H.V. 3.0 Water 150.0Methylparaben 1.0

2 (4-aminophenylsulfonamido) 5-n-butoxymethyl-1,3 ,4-thiadiazole 5.0Kaolin 10.0 Flavor 1.0

Glycerin, q.s., 1.0 liter.

GLYCERIN ELIXIR Grams per Formula: liter Methylparaben 1.0

To prepare the elixir, dissolve trisodium citrate in approximately /1 ofthe glycerine with stirring and warm, if necessary, to facilitatesolution. Add the methylparaben and stir until dissolved. Add thethiadiazole and, if necessary, warm to dissolve. Adjust the volume to 1liter with glycerine and stir until homogenous. Each teaspoon delivers25 mg. of the thiadiazole.

The above formulations are usually administered at a rate of from 2-3tablets or capsules or from 2-3 teaspoons daily, generally with meals.This dos-age, however, may be adjusted (i.e. either increased ordecreased) depending upon the 'severity of the underlying hyperglycemia.

The best mode contemplated by the inventor for carrying out hisinvention will now be set forth as follows:

Example 1 A. Preparation of2-amin0-5-methoxymethyl-1,3,4-thiadiazle.-Stir at room temperature amixture of 0.7 mole of methoxyacetic acid and 0.6 mole ofthiosemicarbazide. Start the drop-wise addition of 0.62 mole ofphosphorus oxychloride and allow the exothermic reaction to bring thereaction temperature to about 60 C. Apply cooling water to hold thereaction temperature at 60-70 C. during the remainder of the addition.When all is added, continue stirring and bring the reaction temperatureto 85-90 C. as rapidly as the foaming and evolution of HCl gas willpermit (i.e. about one hour). Continue stirring at 9095 C. forapproximately 1.5 hours longer until evolution of HCl gas practicallyceases. If the reaction mixture becomes too thick to stir, continueheating without stirring, Dissolve the warm reaction mixture 500 ml. ofwater and stir the solution with about 1.0 g. of decolorizing carbon forabout 10 minutes and filter, Cool the clear filtrate to about 10 C. andmake it basic to pH 9-10 by the gradual addition of 10 molar sodiumhydroxide solution. Allow the crystalline suspension of2-amino-5-methoxymethyl-l,3,4-thiadiazole to stand at 10 C. about onehour, filter and Wash with about 50 ml. of ice water. Dry the filtercake at about 50 C. Obtain additional crude product by extracting theaqueous mother liquors with ethyl acetate and removing the solvent byevaporation.

To purify, dissolve both crops of crude crystals in about 1,000 ml. ofboiling n-butyl acetate. Filter the hot solution and cool the filtrateto 0 -5 C. Separate the resulting pure crystals by filtration and Washwith about 50 ml. of ice cold n-butyl acetate, Dry in air at about 50 C.

B. Preparation of2-(4-amin0phenylsulf0namido)-5-methoxymethyl-l,3,4-triadiaz0le.-Stir amixture of 0.1 mole of Z-amino-S-methoxymethyl-1,3,4-thiadiazole, 0.186mole of dry pyridine and 30 ml. of dioxane at room temperature and add0.11 mole of 4-acetamidobenzenesulfonyl chloride over a period of about20 minutes. When all is added, heat the reaction mixture to about 70 C.and continue stirring at this temperature for about 2.5 hours. Cool thereaction mixture to about 40 C. and pour into a mixture of 100 g. of iceand 300 ml. of water with rapid stirring. Acidity the resultingsuspension to pH 1.0-2.0 by the addition of concentrated hydrochloricacid. Stir the mixture for about 0.5 hour at C., filter and wash thefilter cake with water. Dry at about 60 C. Purify the crude 2 (4acetamidophenylsulfonamido)-5-methoxymethyl- 1,3,4-thiadiazole byrecrystallization from about four times its own weight of 75% methanol.

Hydrolize 0.645 mole of the acetamido derivative from the preceding stepby stirring it With 180 ml. of 7% aqueous hydrochloric acid at 95-l00 C.for about 0.5 hour. Stir the hot solution with 1.0 g. of decolorizingcarbon for about 10 minutes and filter. Cool the filtrate to about 250., add sufiicient 10 molar sodium hydroxide solution to just redissolvethe precipitate and add acetic acid to pH 4.5. Stir the suspension offine crystals at 510 C. for about one hour, filter and wash the filtercake with Water, Dry at about 60 C. Purify the crude2-(4-aminophenylsulfonamido) 5 methoxymethyl-l,3,4-thiadiazole byrecrystallization from about fifteen times its weight of isopropanol.

Example 2 A. Preparation of Z-amin0-5-ethoxymethyl-1,3,4-thiadiazole.Atroom temperature, stir a mixture of 0.384 mole of ethoxyacetic acid and0.362 mole of thiosemicarbazide andstart the dropwise addition of 0.385mole of phosphorous oxychloride. Allow the reaction temperature to riseexothermically to about 60 C. and then apply cooling water to keep thereaction temperature at 60-70 C. during the remainder of the addition.When all is added, continue stirring and slowly heat in a Water bath toraise the reaction temperature to 8590 C. Hold the reaction at thistemperature for about 2.5 hours until evolution of HCl gas practicallyceases. Dissolve the reaction mass in 1.0 liter of water at about 60 C.,stir the solution with about 1.0 g. of decolorizing carbon and filter.Neutralize the clear filtrate to pH 6.5 by the addition of about 40 g.of solid anhydrous sodium carbonate in small portions. Add 110 ml. ofacetic anhydride and stir the mixture for about one hour. Filter theresulting crystalline suspension of practically pureZ-acetamido-S-ethoxymethyl-1,3,4-thiadiazole at 1520 C., wash the filtercake with cold water and dry at about 60 C.

Hydrolyze the acetamido compound by stirring it for about one hour atl00 C. with a mixture of 72 ml. of concentrate hydrochloric acid and 72ml. of water. Dilute the mixture with 50 ml. of water and, whilestirring at 5060 C, make it basic to pH 9.0-9.5 by the addition of aboutml. of 10 molar sodium hydroxide solution. Cool the resultingcrystalline suspension to about 10 C., filter and wash the filter cakewith ice cold water. Dry at about 60 0. Further purify the2-amino-5-ethoxymethyl- 1,3,4-thiadiazole, where desired, byrecrystallization from about four times its weight of n-butyl acetate.

B. Preparation of 2 (4-aminophenylsulfonamido)-5-ethoxymethyl-I,3,4-thiadiazole.-Stir at room temperature a mixture of0.33 mole of 2-amino-5-ethoxymethyl-1,3,4- thiadiazole as preparedabove, 0.7 mole of dry pyridine and 67 ml. of dioxane and 0.32 mole of88% 4-acetamidobenzenesulfonyl chloride over a period of about tenminutes. When all is added, heat the reaction mixture to about 70 C, andcontinue stirring at this temperature for about 3 hours. Cool thereaction mixture to about 40 C., pour into a mixture of 100 g. of iceand 1 liter of water with rapid stirring and acidity the suspension topH 1.0-2.0 by the addition of concentrated hydrochloric acid. Stir themixture for about one hour at 1015 C., filter and wash the filter cakewith water. Dry at about 60 C. Recrystallize the slightly impure 2 (4acetamidophenylsulfonamido)-5-ethoxymethyl-1,3,4-thiadiazole from aboutnine time its own weight of methanol.

Hydrolyze 0.1 mole of the acetamido derivative from the preceding stepby stirring it with 225 ml. of 7% aqueous hydrochloric acid at 95-100 C.for about 2 hours. Stir the hot solution with 1.0 g of decolorizingcarbon for about ten minutes and filter. Cool the clear filtrate toabout 25 C., add sufiicient 10 molar sodium hydroxide solution to justredissolve the precipitate and then add acetic acid to pH 4.5. Stir theresulting suspension at 5-10 C. for about one hour, filter and wash thefilter cake with water. Dry at about 60 C. Recrystallize the crude2-(4-aminophenylsulfonamido)-5-ethoxymethyl-1,3 4-thiadiazole from aboutfive times its weight of 99% isopropanol.

Example 3 A. Preparation of 2-amin0-5-(Z-melhoxyethyl)-1,3,4-thiadiazIe.At room temperature, stir a mixture of 0.625 mole of3-methoxypropionic acid and 0.60 mole of thiosemicarbazide and start thedropWise addition of 0.653 mole of phosphorous oxychloride. Allow thereaction temperature to rise exothermically to about 50 C. and thenapply cooling water to hold the temperature at 4550 C. during theremainder of the addition. When all is added, continue stirring and heatin a Water bath to gradually raise the reaction temperature to about 75C. over a period of about 3 hours and then hold the reaction at thistemperature for an additional hour until evolution of HCl gas ceases.Cool the reaction mixture to about 45 C. and dissolve in 500 ml. ofwater. Stir the solution With about 1 gm. of decolorizing carbon forabout ten minutes and filter. Make the clear filtrate basic to pH 9.09.5by the gradual addition of 10 molar so- :lium hydroxide solution, coolto 10l5 C. and filter. Wash the filter cake with ice cold water and dryat about 50 C. Recrystallize the slightly impure 2-amino-5-(2-methoxyethyl)-l,3,4-thiadiazole from about ten times its weightofn-butyl acetate.

B. Preparation of 2-(4-amin0phenylsulfonamido)-5-(2-"nethoxyethyl)-1,3,4-zhiadiaz0le.Stir a mixture of 0.188 nole of2-amino-5-(2-methoxyethyl)-1,3,4-thiadia2ole as )repared above, 0.633mole of dry pyridine and 75 ml. of lioxane at room temperature and 0.251mole of 91.6% l-acetamidobenzenesulfonyl chloride over a period oflbOllt five minutes. When all is added, heat the reaction nixture toabout 70 C. and continue stirring at this emperature for about 4 hours.Raise the temperature to ibout 80 C. and remove most of the dioxane andex- :ess pyridine by distillation under vacuum. Pour the con- :entratedreaction mixture into 800 ml. of Water, 200 gm. of ice and 50 ml. ofconcentrated hydrochloric acid. ltir the mixture for about one hour atabout 10 C., filter ind Wash the filter cake with water. Dry at about 60C. *urify the crude 2-(4-acetamidophenylsulfonamido)-5-2-methoxyethyl)-1,3,4-thiadiazole from about three imes it weight ofmethanol.

Hydrolize 0.15 mole of the acetamido derivative from he preceding stepby stirring it with 340 ml. of "7% aqueus hydrochloric acid at 95100 C.for about 2 hours. ltir the hot solution with 1 gm. of decolorizingcarbon or about ten minutes and filter. Cool the clear filtrate to bout25 C., add sufficient 10 molar sodium hydroxide olution to justredissolve the precipitate and then add acec acid to ph 4.5. Stir theresulting suspension at -10 i. for about one hour, filter and wash thefilter cake ith water. Dry at about 60 C. and recrystallize the lightlyimpure 2 (4 aminophenylsulfonamido)-5-(2-iethoxyethyl)-1,3,4-thiadiazole from about eight times s weight of 50%methanol.

Example 4 A. Preparation of 2 amino 5-rz-but0xymethyl-l,3,4-1iadiaz0le.Stir at room temperature a mixture of 0.613 role ofn-butoxyacetic acid and 0.6 mole of thiosemicarazide and start thedropwise addition of 0.627 mole of hosphorous oxychloride. Allow theexothermic reaction bring the reaction temperature to about 60 C. thenpply cooling Water to hold the reaction temperature at 360 C. during theremainder of the addition. When 1 has been added, continue stirring andheat in a Water 1th to raise the reaction temperature to 85-90 C. asipidly as foaming and evolution of HCl gas will permit. ontinue stirringat 8590 C. for about one hour longer itil evolution of HCl gas ceases.Dissolve the reaction ixture in 2 liter of Water and 60 C. and add aboutl. of concentrated hydrochloric acid. Stir the solution ith 1 gm. ofdecolorizing carbon and filter at 60 C. 001 the clear filtrate to about30 C. and make it basic pH 9.0-100 by the gradual addition of 10 molarsodium hydroxide solution. Separate the precipitate by filtration, Washthe filter cake with cold water and dry at about 60 C. Purify the crude2-amino-5-n-butoxymethyl-1,3,4-thiadiazole by recrystallization fromabout four times its weight of isopropanol.

B. Preparation of 2-(4-aminophenylsulfonamido)-5-nbutoxymethyl1,3,4-thiadiaz0le.Mix 1.0 mole of 2- amino 5n-butoxymethyl-1,3,4-thiadiazole as prepared above, 3.3 mole of drypyridine and 400 ml. or dioxane. Stir the mixture at room temperatureand add 1.3 moles of 90.6% 4-acetamidobenzenesulfonyl chloride over aperiod of about twenty minutes. When all is added, raise the reactiontemperature to 70 C. over a period of about 2 hours and continuestirring at this temperature for an additional hour. Raise the reactiontemperature to C. and distill off about 50 ml. of the dioxane and excesspyridine under vacuum. Cool the reaction mixture to about 50 C. and pourwith rapid stirring into a mixture of 2 liters of water, 200 gm. of iceand 75 ml. of concentrated hydrochloric acid. Stir the suspension forabout one hour at l520 C., filter and wash the filter cake with about 4liters of Water. Dry at about 60 C. and recrystallize the crude 2('4-acetamidophenylsulfonamido)-5-n-butoxymethyl-1,3,4-thiadiazole fromabout 900 ml. of iospropanol. Concentrate the mother liquor to about ml.and isolate a second crop of crystals. Puri' fy by recrystallizationfrom isopropanol.

Hydrolyze the acetamido derivative from the preceding step by stirringit with a mixture of 1,100 ml. of water, 375 ml. of ethanol and ml. ofconcentrated hydrochlo-ric acid for about 2.5 hours at refluxtemperature. Cool the reaction mixture to 25 C. and add just sufiicient10 molar sodium hydroxide solution to redissolve the precipitate. Filterthe solution, heat the filtrate to 45 C. and acidity to pH 5.0 by thegradual addition of about 55 ml. of glacial acetic acid. Stir theresulting suspension at 25 Cffor about 0.5 hour, filter and Wash thefilter cake with about 1,500 ml. of water. Dry at about 60 C.Recrystallize the crude 2-(4-aminophenylsulfonamido)-S-n-butoxymethyl-l,3,4-thiadiazole from about 20 times its Weight of 50%methanol.

Example 5 A. Preparation of 2-amino-5-(4-methoxyphenyl)-1,3,4-thiadiaz0le.At room temperature, stir a mixture of 0.2 mole of anisicacid, 0.2 mole of thiosemicarbazide and 75 ml. of nitrobenzene and add0.2 mole of phosphorous oxychloride over a period of about ten minutes.When all is added, continue stirring and raise the temperature of thereaction mixture to about 80 C. over a period of one hour. Hold thereaction mixture at this temperature for about 4 hours until evolutionof HCl gas ceases. Cool the reaction mixture to about 50 C., stir with amixture of 3 liters of Water and 100 ml. of concentrated hydrochloricacid and remove the nitrobenzene by steam distillation. Stir theresulting solution with about 5 gm. of decolorizing carbon for tenminutes and filter While hot. Make the clear filtrate basic to pH 8.0 bythe gradual addition of 10 molar sodium hydroxide solution, cool to 20C. and filter, Wash the filter cake with water and dry at about 60 C.

B. Preparation of 2-(4-aminophenylsulfonamido)-5-(4- methoxyphenyl)1,3,4 thiadiaz0le.-Stir a mixture of 0.145 mole of2-amino-5-(4-methoxyphenyl)-1,3,4-thiadiazole as prepared above, 0.5mole of dry pyridine and 70 ml. of dioxane at room temperature and add0.2 mole of 91% 4-acetamidobenzenesulfonyl chloride over a period offive minutes. When all is added, continue stirring and raise thetemperature of the reaction mixture to 80 C. over a period of twentyminutes and then continue stirring at 75-80 C. for an additional 2hours. Remove the dioxane and excess pyridine by distillation undervacuum. Stir the concentrated reaction mixture with 300 ml. of water, 20ml. of concentrated hydrochloric acid and 100 gm. of ice. Continuestirring at 15-20 C. until a uniform dispersion is obtained, filter,wash the filter cake with water and dry at about 60 C.

Hydrolyze 0.1 mole of the practically pure2-(4-acetamidophenylsulfonamide)-5-(4 methoxyphenyD-l,3,4-thiadiazolefrom the preceding step by stirring it at reflux temperature with amixture of 200 ml. of ethanol and 50 ml. of concentrated hydrochloricacid for about 4 hours. Dilute the reaction mixture with 600 ml. ofwater and add molar sodium hydroxide solution to just redissolve theprecipitate. Add acetic acid to pH 4.5, filter and wash the filter cakewith water. Dry at about 60 C. Purify the crude2-(4-aminophenylsulfonamido)-5-(4-methoxyphenyl)-1,3,4-thiadiazole byrecrystallization from about fourteen times its weight of ethyleneglycol monoethyl ether.

Example 6 A. Preparation of 2-amin0-5-is0pr0p0xymethyl-1,3,4-thiadiazole.-Stir a mixture of 0.45 mole of isopropoxyacetic acid and0.432 mole of thiosemicarbazide at room temperature and start thedropwise addition of 0.47 mole of phosphorous oxychloride. Allow thereaction temperature to rise exothermically to about 60 C. and thenapply cooling water to hold the temperature at -60 C. during theremainder of the addition. When all is added, continue stirring and heatin a Water bath to raise the reaction temperature to 8590 C. as rapidlyas foaming and evolution of HCl gas will permit. Continue stirring at85-90 C. for about one hour longer until evolution of HCl gas ceases.Dissolve the reaction mixture in 800 ml. of water at C., stir thesolution for 15 minutes with 5 gm. of decolorizing carbon and filter.Cool the clear filtrate to about 25 C. and make it basic to pH 9.0-10.0by the gradual addition of 10 molar sodium hydroxide solution. Filter01f the precipitate at about 20 C., wash with water and dry at about 60C. Recrystallize the crude 2-amino-5- isopropoxymethyl-1,3,4-thiadiazolefrom about eight times its weight of n-butyl acetate.

B. Preparation of 2-(4-amin0phenylsulfonamido)-5-isopropoxymethyl-I,3,4-thiadiazole.-Mix 0.25 mole of 2-amino-5-isopropoxymethyl-1,3,4-thiadiazole as prepared above, 0.84 moleof dry pyridine and 100 ml. of dioxane. Stir the mixture at roomtemperature and add 0.325 mole of 90.6% 4-acetamidobenzenesulfonylchloride over a period of about ten minutes. When all is added, heat thereaction mixture to 60 C. and continue stirring at this temperature forabout 3 hours. Raise the temperature to C. and apply vacuum to removeabout 100 ml. of the solvent by distilliation. Pour the residue into amixture of one liter of water, 500 gm. of ice and 25 ml. of concentratedhydrochloric acid with rapid stirring. Continue stirring at 510 C. forabout 0.5 hour. Filter the mixture, wash the filter cake with water anddry at 60 C.

Hydrolyze 0.22 mole of the practically pure2-(-acetamidophenylsulfonamido)-5-isopropoxymethyl-1,3,4 thiadiazolefrom the preceding step by stirring it with 500 ml.

of 7% hydrochloric acid and 50 ml. of methanol at C. for about 2 hours.Stir the hot solution with 2 gm. of decolorizing carbon for about tenminutes and filter. Cool the clear filtrate to about 25 0., addsuflicient 10 molar sodium hydroxide solution to just redissolve theprecipitate then add acetic acid to pH 4.5. Stir the resultingsuspension at 5-10 C. for about one hour, filter and wash the filtercake with water. Dry at about 60 C. Recrystallize the crude2-(4-aminophenylsulf0namido)-5-isopropoxymethyl-1,3,4-thiadiazole fromabout twenty times its weight of 50% methanol.

I claim:

1. 2 (4-aminophenylsulfonamido) 1,3,4 thiadiazole having at the5-position a lower alkoxy-lower alkyl group.

2. The compound 2-(4 aminophenylsulfonamido) 5-methoxymethyl-1,3,4-thiadiazole.

3. The compound 2-(4 aminophenylsulfonamido) 5-ethoxymethyl-1,3,4-thiadiazole.

4. The compound 2-(4 aminophenylsulfonamido) 5- (2-methoxyethyl)-1,3,4-thiadiazole.

5. The compound2-(4-aminophenylsulfonamido)-5-nbutoxymethyl-l,3,4-thiadiazole.

6. The compound 2-(4 aminophenylsulfonamido) 5-isopropoxymethyl-1,3,4-thiadiazole.

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851,277 10/ 1960 Great Britain.

858,189 1/1961 Great Britain.

OTHER REFERENCES German Auslegeschrift 1,067,440, Oct. 22, 1959. GermanAuslegeschrift 1,079,061, Apr. 7, 1960. Chemical Abstracts, vol. 40,columns 1593 to 1994 (1946) (abstracts of Bovet et al. and Loubatieres).

ONeal et al.: J. of Med. and Pharm. Chem, vol. 5, pages 617 to 626 (May1962).

JOHN D. RANDOLPH, Primary Examiner.

IRVING MARCUS, WALTER A. MODANCE,

Examiners.

E. E. BERG, Assistant Examiner.

1. 2- (4-AMINOPHENYLSULFONAMIDO) - 1,3,4- THIADIAZOLE HAVING AT THE5-POSITION A LOWER ALKOXY-LOWER ALKYL GROUP.